(i) Field of the Invention
The present invention relates to the cognitive enhancement through the administration of synergistic drugs.
(ii) Background of the Invention
Various disorders and diseases exist which affect cognition. Cognition can be generally described as including at least three different components: attention, learning, and memory. Each of these components and their respective levels affect the overall level of a subject""s cognitive ability. For instance, while Alzheimer""s Disease patients suffer from a loss of overall cognition and thus deterioration of each of these characteristics, it is the loss of memory that is most often associated with the disease. In other diseases patients suffer from cognitive impairment that is more predominately associated with different characteristics of cognition, for instance Attention Deficit Hyperactivity Disorder (ADHD), focuses on the individual""s ability to maintain an attentive state. Other conditions include general dementias associated with other neurological diseases, aging, and treatment of conditions that can cause deleterious effects on mental capacity, such as cancer treatments, stroke/ischemia, and mental retardation. The present invention is directed toward the treatment of these and other similar disorders through the repair or amelioration of the cognitive deficits or impairments.
Cognition disorders create a variety of problems for today""s society. Therefore, scientists have made efforts to develop cognitive enhancers or cognition activators. The cognition enhancers or activators that have been developed are generally classified to include nootropics, vasodilators, metabolic enhancers, psychostimulants, cholinergic agents, biogenic amines drugs, and neuropeptides. Vasodilators and metabolic enhancers (e.g. dihydroergotoxine) are mainly effective in the cognition disorders induced by cerebral vessel ligation-ischemia; however, they are ineffective in clinical use and with other types of cognition disorders. Of the developed cognition enhancers, typically only metabolic drugs are employed for clinical use, as others are still in the investigation stage. Of the nootropics for instance, piracetam activates the peripheral endocrine system, which is not appropriate for Alzheimer""s Disease due to the high concentration of steroids produced in patients while tacrine, a cholinergic agent, has a variety of side effects including vomiting, diarrhea, and hepatotoxicity.
Ways to improve the cognitive abilities of diseased individuals have been the subject of various studies. Recently the cognitive state related to Alzheimer""s Disease and different ways to improve patient""s memory have been the subject of various approaches and strategies. In the case of Alzheimer""s Disease, efforts to improve cognition, typically through the cholinergic pathways or though other brain transmitter pathways, have been investigated. This approach relies on the inhibition of acetyl cholinesterase enzymes through drug therapy. Acetyl cholinesterase is a major brain enzyme and manipulating its levels can result in various changes to other neurological functions and cause side effects. Cholinesterase inhibitors only produce some symptomatic improvement for a short time. Additionally, the use of cholinergic inhibitors only produces an improvement in a fraction of the Alzheimer""s Disease patients with mid to moderate symptoms and is thus only a useful treatment for a small portion of the overall patient population. As a result, use of the cholinergic pathway for treatment of cognitive impairment, particularly in Alzheimer""s Disease, has proven to be inadequate. Additionally, current treatments for cognitive improvement are limited to specific neurodegenerative diseases and have not proven effective in treatment across a broad range of cognitive conditions.
With regard to normal and abnormal memory both K+ and Ca2+ channels have been demonstrated to play key roles in memory storage and recall. For instance, potassium channels have been found to change during memory storage. (Etcheberrigaray, R., et al. (1992) Proceeding of the National Academy of Science 89:7184; Sanchez-Andres, J. V. and Alkon, D. L. (1991) Journal of Neurobiology 65:796; Collin, C., et al. (1988) Biophysics Journal 55:955; Alkon, D. L., et al. (1985) Behavioral and Neural Biology 44:278; Alkon, D. L. (1984) Science 226:1037). This observation, coupled with the almost universal symptom of memory loss in Alzheimer""s patients, led to the investigation of ion channel function as a possible site of Alzheimer""s Disease pathology, modulation by PKC, and its overall effect on cognition.
There still exists a need for the development of methods for the treatment for improved overall cognition, either through a specific characteristic of cognitive ability or general cognition. There also still exists a need for the development of methods for the improvement of cognitive enhancement whether or not it is related to a specific disease state or cognitive disorder. The methods and compositions of the present invention are needed and will greatly improve the clinical treatment for diminished cognitive ability whether related to a specific neurodegenerative disease, hypoxia, stroke or similar disorder. The methods and compositions also provide treatment and/or enhancement of the cognitive state.
The present invention relates to compounds, compositions, and methods for the treatment of conditions associated with the impairment of cognitive ability. In a preferred embodiment, the present invention further relates to compounds, compositions and methods for the treatment of conditions associated with neurodegenerative diseases, such as Alzheimer""s Disease, memory dysfunction, and ischemia/stroke. Treatment provides for improved/enhanced cognitive ability. In another embodiment the present invention relates to compounds, compositions, and methods for the improvement/enhancement of cognitive ability.
In another aspect the present invention relates to the combination of a methylxanthine and carbonic anhydrase activators, to alter or test distinct molecular cascades, either in vivo or in vitro, in order to provide enhanced cognitive response. In a preferred embodiment the carbonic anhydrase activator is phenylalanine. In a preferred embodiment the methylxanthine is selected from theophylline and caffeine. Enhanced cognitive response, for example, can be employed in the treatment of Alzheimer""s Disease.
Another aspect of the present invention relates to a method for treating conditions related to hypoxia and improving/enhancing the cognitive state of the subject comprising administering to the subject an effective amount of a composition combining a methylxanthine and a carbonic anhydrase activator. In a preferred embodiment the carbonic anhydrase activator is phenylalanine. In a preferred embodiment the methylxanthine is selected from theophylline and caffeine.
Another aspect of the present invention relates to a composition for improving/enhancing cognitive ability comprising: (i) an effective amount of a combination of a methylxanthine and a carbonic anhydrase activator; and (ii) a pharmaceutically effective carrier. In a preferred embodiment the carbonic anhydrase activator is phenylalanine. In a preferred embodiment the methylxanthine is selected from theophylline and caffeine. In a preferred embodiment the composition is used to improve/enhance cognitive ability associated with Alzheimer""s Disease or stroke/ischemia. In another embodiment, the combination is delivered to subjects or models of Alzheimer""s Disease or stroke/hypoxia.
In one embodiment of the invention the combination of a methylxanthine and a carbonic anhydrase activator results in improved cognitive abilities. In a preferred embodiment the carbonic anhydrase activator is phenylalanine. In a preferred embodiment the methylxanthine is selected from theophylline and caffeine. In one embodiment the improved cognitive ability is memory. In another embodiment the improved cognitive ability is learning. In another embodiment the improved cognitive ability is attention.
Another embodiment of the invention is a method of improving cognitive ability through the combination of a methylxanthine and a carbonic anhydrase activator. In another embodiment of the invention the combination of a methylxanthine and a carbonic anhydrase activator is delivered to xe2x80x9cnormalxe2x80x9d subjects. In another embodiment of the invention the combination of theophylline and a carbonic anhydrase activator is delivered to subjects suffering from a disease, deteriorating cognitive faculties, or malfunctioning cognition. In a preferred embodiment the method is a method for treating Alzheimer""s Disease cognitive degeneration. In a preferred embodiment the carbonic anhydrase activator is phenylalanine. In a preferred embodiment the methylxanthine is selected from theophylline and caffeine.
In a preferred embodiment of the invention the combination of a methylxanthine and a carbonic anhydrase activator is administered through oral and/or injectable forms including intravenously and intraventricularly. In another embodiment the combination may be administered through a sports drink or as a food supplement. In a preferred embodiment the carbonic anhydrase activator is phenylalanine. In a preferred embodiment the methylxanthine is selected from theophylline and caffeine.
The present invention therefore provides methods of treating impaired memory or a learning disorder in a subject, the method comprising administering thereto a therapeutically effective amount of a methylxanthine and a carbonic anhydrase activator. The compounds can thus be used in the therapeutic treatment of clinical conditions in which memory defects or impaired learning occur. In this way memory and learning can be improved and the condition of the subject can thereby be improved.
The present invention is also particularly suited to administration, particularly oral administration, since the combination of a methylxanthine (e.g. theophylline) and a carbonic anhydrase activator would be associated with a specific blood brain barrier transporter (BBB). In a preferred embodiment the transporter is the BBB transporter for phenylalanine.
The compositions and methods have utility in treating clinical conditions and disorders in which impaired memory or a learning disorder occurs, either as a central feature or as an associated symptom. Examples of such conditions which the present compounds can be used to treat include Alzheimer""s Disease, multi-infarct dementia and the Lewy-body variant of Alzheimer""s Disease with or without association with Parkinson""s Disease; Creutzfeld-Jakob Disease, Korsakow""s disorder, attention deficit hyperactivity disorder, hypoxia, ischeamic stroke, mental retardation, general dementia, and xe2x80x9csundownxe2x80x9d syndrome.
The compositions and methods can also be used to treat impaired memory or learning which is age-associated, is consequent upon electro-convulsive therapy or which is the result of brain damage caused, for example, by stroke, an anesthetic accident, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication or a vitamin deficiency.
The pharmaceutical compositions and methods according to the invention are useful in the enhancement of cognition, prophylaxis and/or treatment of cognition disorders, wherein cognition disorders include, but are not limited to, disorders of learning acquisition, memory consolidation, and retrieval, as described herein.